Racemic mexiletine has been administered orally to relieve the symptoms of a number of painful neuropathies including painful diabetic neuropathy; Dejard, et al., Mexiletine for treatment of chronic painful diabetic neuropathy, The Lancet, 2:9, 9-11 (1988); pain due to acute or chronic nerve injury; Tanelian, et al., Neuropathic pain can be relieved by drugs that are use-dependent sodium channel bockers, lidocaine, carmazepine and mexiletine, Anesthesiology, 74: 949-951 (1991); alcoholic polyneuropathy; Sakuta, et al., Mexiletine for painful alcholic neuropathy, Internal Medicine, 34: 577-579 (1995); chronic pain associated with radiation therapy; Colclough, et al., Mexiletine for chronic pain, The Lancet, 342: 1484-1485 (1993); thalamic pain syndrome, Awerbuch, G. I., et al., Mexiletine for thalamic pain syndrome, Intern. J., Neuroscience, 55:129-133 (1990); and diabeic truncal pain; Kubota, K., et la., Relief of severe diabetic truncal pain with mexiletine, J. Med., 22: 307-310 (1991).
The overall metabolic disposition of mexiletine enantiomers in healthy human subjects is non-stereoselective; McErlane et al., Xenobiotica, 25(10):1127-1145 (1995). However, another study of stereoselective glucuronidation of enantiomers of mexiletine suggests a stereoselective glucuronidation of the (R)-enantiomer. Grech Belanger, et al., Stereoselective disposition of mexiletine in man, Br. J. Clin. Pharmacol., 21:481-487 (1986). The cardiac electrophysiological effect of mexiletine in rats and dogs is also stereospecific. Hill demonstrated the binding affinity of (R)-mexiletine is twice that of (S)mexiletine for cardiac sodium channels. Hill, R. J. et al., Determinants of stereospecific binding of type I antiarrhythmic drugs to cardiac sodium channels, Molec. Pharmacol., 34:659-663 (1988).
Racemic mexiletine is also an antiarrhythmic agent and studies have shown that the (R)-enantiomer exhibits greater antiarrhythmic properties than the (S)-enantiomer in dogs. Turgeon, J. et al., Resolution and Electrophysiological effects of mexiletine enantiomers, J. Pharm. Pharmacol., 43:630-635 (1991).
While racemic mexiletine has shown efficacy for a variety of painful neuropathies, its proarrhythmic properties are a cause for concern as are a number of serious non-cardiac adverse side effects all of which limit its use. Such effects include tremors, diplopia, nausea and vomiting, and occur in up to 70 percent of patients. These adverse side effects are closely related to the plasma concentration of racemic mexiletine, and such adverse effects are usually lessened with reductions in dosage. However, reduced dosage often results in reduced therapeutic efficacy. Campbell, R. W. F., Mexiletine, N. Eng. J. Med., 316:29-34 (1987).
Thus, an improved method of treating neuropathic pain with a sodium channel blocker that has reduced or eliminated adverse side effects is greatly desired.